Basics of Transplantation Medicine

Maria Kaisar Researcher in Transplantation Science

NHS Blood and Transplant & Nuffield Department of Surgical Sciences

Treatment for end stage organ diseases .Heart, lungs, liver, kidney, pancreas, bowel

Improves quality of life for organ recipients

Economic benefit when compared with long term treatment Historical overview

Prior to World War II Improvements in surgical techniques had made transplantation possible- Rejection was insuperable. 1936 George David Snell; compatibility of tumor cells in mice 1937 Peter Gorer and George Snells HLA system 1940 Studies on skin transplantation

1941 War adversity inspired Sir to further his research in immunology

1960 Nobel Prize awarded to Sir Peter Medawar Historical overview

• 1954 Boston; , John Merrill & Hartwell Harrison performed the first successful live human kidney transplant, between identical twins and with long-term survival

• 1960 UK's first live human kidney transplant by Sir Michael Woodruff

• 1962 Boston; Joe Murray and Roy Calne performed the first successful deceased donor kidney transplant

• 1965 The world’s first transplant unit was established in

• 1965 Terasaki's group, in the USA proposed leucocyte HLA antigen matching as tests for donor - recipient selection

• 1967 First liver and heart transplants by & Christian Barnard

• 1978 Cyclosporine was first introduced as immunosuppressant by Sir Roy Calne Transplants are generally “foreign”

 Autografts - skin grafts from one site to another on the same individual

 Isografts or syngeneic transplants - between monozygotic twins

 Allograft or allogeneic transplants - between two genetically distinct individuals

 Xenografts (foreign) - grafts obtained from a different species from the recipient Donor types

 Donation after Brain Death (DBD): Cerebral injury followed by herniation of brain stem

 Donation after Circulatory Arrest (DCD): Futile medical treatment and withdrawal of support

 Living donors (LD): Relatives, spouses, friends, altruistic donors Preservation Transplantation Process

Patient Donor Organs Recipient

Donor Management Organ Organ Brain Death & Cardiac Arrest Procurement Preservation Organ transplantation immunological vs non immunological factors

Advancing Transplantation: New Questions, New Possibilities in kidney and Jonas Wadström et al., Transplantation 2017 Feb;101 Impact of immunological factors on survival Immune rejection of transplants

• Hyperacute rejection

• Acute rejection

• Chronic rejection Hyperacute graft rejection

• Pre-existing antibodies against blood group & HLA expressed on the graft lead to rapid organ rejection

• ABO antigens are expressed on all tissues including vascular endothelial cells

• HLA class I molecules are expressed on all cells

• Occurs in minutes and is complement dependent Hyperacute rejection Pre-existing antibodies bind to donor ABO antigens Figure 13-36 Inflammatory response elicits from pre existing Abs in the recipient that bind to donor ABO antigens causing occlusion of blood vessels Hyperacute graft rejection

• Hyperacute rejection leads to graft loss within minutes

• ABO-matching and ‘cross-matching’ donor and recipient can prevent hyperacute rejection

• Cross-matching determines whether the recipient has pre-existing antibodies against donor leukocytes Acute rejection Acute skin graft rejection mediated by T cells Figure 13-36 Acute rejection of graft with HLA mismatch

• Alloreactive T cells cause rejection

• Inflamed Graft • swollen • necrosis • develops over days

• Therapautic options • Immunosupressive regime aims to reduce T cell activation Acute rejection Direct pathway of allorecognition

Donor dendritic cells are recognised by recipient T cells Acute rejection • Recipient T cell recognition of donor DCs

• T cells activation upon recognition of allogeneic HLA class I or class II (direct allorecognistion)

• Effector CD8 T cells proliferation

• Effector TH1 cells activate macrophages to produce inflammatory cytokines (IL-1, IL-6, TNFa) Acute rejection Direct & Indirect allorecognition of HLA antigens

Indirect

Graft derived proteins are taken up and processed by the recipient DC and are presented by self (recipient) MHC class I or II molecules. Non immunological triggers for organ failure and graft dysfunction Challenges in solid organ transplantation immunological vs non immunological factors

Advancing Transplantation: New Questions, New Possibilities in kidney and Liver Transplantation Jonas Wadström et al., Transplantation 2017 Feb;101 Non-immunological factors

• Donor age- Independent predictor of transplantation outcomes

• Hypothermic preservation- the period between and graft reperfusion in the recipient; the main cause of ischaemia reperfusion injury

Patient Donor Organs Recipient

Organ Preservation No circulation-Oxygen starvation Non-immunological factors

• Ischaemia and reperfusion is a pathological condition characterized by an initial restriction of blood supply to an organ followed by the sub- sequent restoration of perfusion and reoxygenation.

• Limited or no oxygen delivery in the organ dysregulates metabolic activity on the cellular level • Tissue hypoxia • Endothelia activation • Production of reactive oxygen species

• Restoration of oxygenation promotes tissue injury and extensive inflammatory response Non immunological triggers for graft dysfunction Ischemia and reperfusion triggers a pathological activation of the

H K Eltzschig & Tobias Eckle, Ischemia and reperfusion- from mechanism to translation Nat Med. 2011 Nov 7; 17(11) Chronic graft rejection

. Reflects a slow loss of graft function

. Interplay of immunological and non immunological factors

. Donor organ quality has a long term impact on the transplant

. Correlates with the presence of antibodies

. Long term impact of ischemia-reperfusion injury Conclusions

 Organ transplantation is a life saving and life transforming treatment of end stage disease

 Transplantation outcomes depend on a range of factors related to donor, graft and recipient

 Great achievements in Transplantation Medicine the last few decades have improved allograft function for organ recipients